Metformin as a protective agent against natural or chemical toxicities: a comprehensive review on drug repositioning.

BACKGROUND: Metformin is the first prescribed drug for hyperglycemia in type 2 diabetes mellitus. Mainly by activating AMPK pathway, this drug exerts various functions that among them protective effects are of the interest. PURPOSE: Herein, we aimed to gather data about the protective impacts of metformin against various natural or chemical toxicities. RESULTS: An extensive search among PubMed, Scopus, and Google Scholar was conducted by keywords related to protection, toxicity, natural and chemical toxins and, metformin. Our literature review showed metformin alongside its anti-hyperglycemic effect has a wide range of anti-toxic effects against anti-tumour and routine drugs, natural and chemical toxins, herbicides and, heavy metals. CONCLUSION: It is evident that metformin is a potent drug against the toxicity of a broad spectrum of natural, chemical toxic agents which is proved by a vast number of studies. Metformin mainly through AMPK axis can protect different organs against toxicities. Moreover, metformin preserves DNA integrity and can be an option for adjuvant therapy to ameliorate side effect of other therapeutics.

Magnetic Stent Removal in a Nurse Led Clinic; a Nine Month Experience.

Ureteric stents are frequently inserted post endourological procedures. However, subsequent endoscopic stent removal requires a second procedure for the patient and the availability of necessary resources. Longer duration of indwelling stents can lead to increased risk of symptoms and complications. The use of magnetic stents removed with a magnetic retrieval device (BlackStar©), offers an alternative which obviates the need for cystoscopy. We assessed the outcomes for this novel method of stent removal in our institution. A retrospective analysis was performed of all patients undergoing magnetic stent insertion and subsequent removal in a nurse-led clinic over a nine-month period. Patients were followed up with a prospective validated Ureteral Stent Symptoms Questionnaire (USSQ)3. A cost analysis was also performed. In total, 59 patients were treated using magnetic stents. The complication rate was low (6.7%). The median duration of indwelling stent was 5.8 days (range 1-11 days). Patients reported haematuria and lower urinary tract symptoms but >90% experienced no functional impairment with minimal days of employment lost (mean 0.75 days). All patients reported satisfaction with nurse-led stent removal and 97% were happy to have stents removed via this method in the future. The total financial savings were estimated at €47,790 over this period. Nurse-led removal of magnetic stents is safe and well tolerated by patients and enables expedient stent removal. It also provides a significant cost benefit and frees up valuable endoscopic resources.

Cycling and spinal trauma: A worrying trend in referrals to a national spine centre.

INTRODUCTION: Cycling has seen a large increase in popularity worldwide over the last number of years. This has been linked to an increase in the number of road traffic accidents involving cyclists. Participation in cycling as part of competitive sport and endurance events has seen particular growth. AIM: To examine patients referred with spinal trauma related to cycling and to assess whether the growing popularity of cycling and particularly competitive cycling is linked to an increase in spinal trauma. METHODS: A retrospective analysis was carried out of a prospectively maintained database of referrals to a national referral centre for spinal trauma over a 4-year period (2010-2013). Data were further analysed for years 2012-2013, as there were incomplete data for years 2010-2011. RESULTS: Spinal injuries involving cyclists increased by 200% from 2010 to 2013. In comparison those involving cars only increased by 29% and motorcycles reduced by 68%. From 2012 to 2013 there were 24 cyclist trauma referrals. The most common level injured was cervical spine (71%). Five patients (20.8%) had neurological deficit with 12.5% complete paralysis ASIA A disability score. The spinal fixation rate was 29.1%, 16.6% were managed with a HALO device. In total, 25% of patients were injured whilst training on a racer style bicycle, including all of the patients with complete spinal cord injury. CONCLUSION: There has been a significant increase in spinal trauma due to cycling accidents over this four year period. Competitive cycling has been a factor in the most severely injured patients. Increased public awareness campaigns for those participating in cycling for sport may be warranted.

Initial experience with a dual-console robotic-assisted platform for training in colorectal surgery.

BACKGROUND: Minimally invasive surgery is associated with several patient-related benefits, including reduced length of hospital stay and reduced blood loss. Robotic-assisted surgery offers many advantages when compared with standard laparoscopic procedures, including a stable three-dimensional binocular camera platform, motion smoothing and motion scaling, improved dexterity and ergonomics. There are limited data on the effectiveness of the dual-console DaVinci Xi platform for teaching resident surgeons. The goal of this study was to examine preliminary outcomes following the introduction of a dual-console robotic platform in our institution. METHODS: A retrospective review of our prospectively maintained patient database was performed. The first ten dual-console resident-performed procedures in colorectal surgery were compared with matched cases performed on a single console by the trainer. Patient demographics, operative times and patient outcomes were compared. RESULTS: Twenty patients were included in this study. There was no significant difference in console time (p = 0.46) or total operative time (p = 0.52) when residents and trainers were compared. Patient outcomes were equivalent, with no difference in length of stay, morbidity or mortality. CONCLUSIONS: The DaVinci Xi dual-console platform is a safe and effective platform for training junior surgeons. The dual-console system has the potential to alter surgical training pathways.

The effect of Rapid Access Prostate Clinics on the outcomes of Gleason 7 prostate cancer: does earlier diagnosis lead to better outcomes?

INTRODUCTION: Rapid Access Prostate Clinics (RAPC) were introduced in Ireland by the National Cancer Control Programme bringing about expedited referral pathways and increased detection rates of prostate cancer. Lower Gleason (G) grade at diagnosis due to RAPC has been previously reported but grade at prostatectomy has not been assessed. The aim of this study was to assess the impact of RAPC on the outcomes of patients with G7 disease on radical prostatectomy (RP). METHODS: A retrospective analysis was carried out of all RPs performed over a 9-year period (2006-2014). Outcomes for G7 prostatectomies were compared before and after the introduction of the RAPC, with a further sub-analysis of G4 + 3 versus G3 + 4. The primary outcome was biochemical recurrence (BCR). Other outcomes were adjuvant/salvage radiotherapy, extra prostatic extension, positive surgical margins, seminal vesicle involvement and tumour stage. RESULTS: In total, 240 RPs were performed with 167 cases graded G7 (70 graded G4 + 3 and 97 graded G3 + 4). Since the introduction of RAPC the proportion of G4 + 3 compared to G3 + 4 has increased from 37.9 to 42%. There was no statistical difference in outcomes for G4 + 3 treated before and after the introduction of RAPC. G4 + 3 was associated with higher rates of BCR (24.4 vs. 0%, p < 0.0001, radiotherapy (41.1 vs. 4.8%, p < 0.0001) and worse histological features than G3 + 4. CONCLUSION: Despite the benefits in diagnosis of prostate cancer brought about by RAPC in Ireland, this has not translated to a lower grade for surgically treated patients. There has been no improvement in outcomes especially for higher grade G4 + 3 disease.

Endovenous radiofrequency ablation: no value in short-term duplex ultrasound follow-up.

INTRODUCTION: Endogenous radiofrequency ablation (RFA) is a proven treatment for varicose veins that has equal efficacy to surgical stripping. It offers the benefit of reduced post operative pain and wound infection and quicker return to work. AIM: To carry out a clinical audit of patients undergoing RFA to monitor outcomes, complication rates, follow-up sclerotherapy and to assess the need for post-operative duplex scan. METHODS: A retrospective analysis was performed of 174 procedures carried out from January 2011 to March 2012. Patients were pre-assessed with history, physical exam and duplex ultrasound. They were followed up at 3 months with same. CEAP classification was applied to check for post-operative improvement. RESULTS: 174 procedures, including 165 great saphenous vein and 9 short saphenous vein ablations were carried out on 154 patients. The duplex occlusion rate at 3 months was 99 %. 141 patients (81 %) showed a reduction in CEAP score with average CEAP decreasing from 2.37 to 0.96. Overall the complication rate was low at 7 %. Paraesthesia was the most common complication with 7 cases (4 %). There were no DVTs. 45.4 % of patients went on to have follow-up sclerotherapy for venous flares. CONCLUSION: RFA is a safe and effective treatment for varicose veins. There is no benefit in performing routine short term follow-up duplex scan due to the high occlusion rates.

Evaluating the clinical efficacy and cost effectiveness of direct access endoscopy.

INTRODUCTION: Direct access endoscopy (DAE) allows primary care physicians (PCPs) to refer patients with concerning symptoms for endoscopy in a timely manner. Guidelines are available to assist PCPs in appropriately selecting patients for DAE. The objective of this study was to evaluate both the clinical benefit and cost effectiveness of an upper gastrointestinal (UGI) DAE program. METHODS: The diagnostic yield of DAE patients attending for UGI studies was evaluated using a prospectively maintained database from 2004 to 2011. The diagnosis of UGI neoplasia, Barretts oesophagus, peptic ulcer disease or other conditions were recorded. In addition the age of the patient and the indication for the UGI endoscopy as per the PCP was compared with National Institute of Clinical Excellence (NICE) guidelines for UGI endoscopy. RESULTS: PCPs referred 4262 patients for UGI endoscopy. Oesophageal cancer was diagnosed in 7 and gastric cancer was identified in 27 patients. This represents a diagnostic yield overall of 0.8% for UGI cancers. Barretts oesophagus was identified in 148 (3.5%) and 185 patients (4.34%) were diagnosed with peptic ulcer disease. Interestingly, 3734 patients (87.6%) had a normal UGI endoscopy through our DAE program representing a cost of 2,296,410 Euro. In patients under 40 years of age the diagnostic yield for UGI cancer was 0.14%. More importantly, 92.2% of UGI endoscopies in patients less 40 years of age were normal. CONCLUSION: It is essential that PCPs adhere to published guidelines prior to referring patients to the DAE program. Furthermore, patients under 40 years of age may represent a subset of patients that may not benefit from immediate UGI endoscopy through a direct access program.

Endochondral bone formation is involved in media calcification in rats and in men.

Arterial media calcification is often considered a cell-regulated process resembling intramembranous bone formation, implying a conversion of vascular tissue into a bone-like structure without a cartilage intermediate. In this study, we examined the association of chondrocyte-specific marker expression with media calcification in arterial samples derived from rats with chronic renal failure (CRF) and from human transplant donors. CRF was induced in rats with a diet supplemented with adenine. Vascular calcification was evaluated histomorphometrically on Von Kossa-stained sections and the expression of the chondrocyte markers sox9 and collagen II with the osteogenic marker core-binding factor alpha1 (cbfa1) was determined immunohistochemically. Media calcification was detected in more than half of the rats with CRF. In over half of the rats with severe media calcification, a typical cartilage matrix was found by morphology. All of the animals with severe calcification showed the presence of chondrocyte-like cells expressing the markers sox9, collagen II, and cbfa1. Human aorta specimens showing mild to moderate media calcification also showed sox9, collagen II, and cbfa1 expression. The presence of chondrocytes in association with calcification of the media in aortas of rats with CRF mimics endochondral bone formation. The relevance of this association is further demonstrated by the chondrogenic conversion of medial smooth muscle cells in the human aorta.

Uremia-related vascular calcification: more than apatite deposition.

In the present study, we characterized and compared the mineral phase deposited in the aortic wall of two different frequently used chronic renal failure rat models of vascular calcification. Vascular calcification was induced in rats by either a 4-week adenine treatment followed by a 10-week high-phosphate diet or 5/6 nephrectomy followed by 6 weeks of 0.25 microg/kg/day calcitriol treatment and a high-phosphate diet. Multi-element mapping for calcium and phosphate together with mineral identification was performed on several regions of aortic sections by means of synchrotron X-ray-mu-fluorescence and diffraction. Bulk calcium and magnesium content of the aorta was assessed using flame atomic absorption spectrometry. Based on the diffraction data the Von Kossa-positive precipitate in the aortic regions (N=38) could be classified into three groups: (1) amorphous precipitate (absence of any diffraction peak pattern, N=12); (2) apatite (N=16); (3) a combination of apatite and magnesium-containing whitlockite (N=10). The occurrence of these precipitates differed significantly between the two models. Furthermore, the combination of apatite and whitlockite was exclusively found in the calcitriol-treated animals. These data indicate that in adenine/phosphate-induced uremia-related vascular calcification, apatite is the main component of the mineral phase. The presence of magnesium-containing whitlockite found in addition to apatite in the vitamin D-treated rats, has to be seen in view of the well-known vitamin D-stimulated gastrointestinal absorption of magnesium.

Bisphosphonates prevent experimental vascular calcification: Treat the bone to cure the vessels?

Bisphosphonates are inhibitors of bone resorption that are widely used to treat osteoporosis. Price and colleagues demonstrate that ibandronate suppressed the development of uremia-related vascular calcification in rats. These findings extend the link between bone remodeling and vascular calcification to the context of chronic renal failure, opening perspectives toward novel therapeutic strategies.

Improving the yield of Mozzarella cheese by phospholipase treatment of milk.

Part-skim Mozzarella cheese was manufactured from milk hydrolyzed with fungal phospholipase A1 prior to renneting. The phospholipase treatment reduced fat losses in whey and cooking water and increased cheese yield as a result of improved fat and moisture retention in the cheese curd. The amount of phospholipids in the whey was reduced because of improved retention of lysophospholipids in the cheese curd. Water binding in the fresh curds and young cheeses up to 3 wk of storage was investigated by a 1H nuclear magnetic resonance spin-spin relaxation technique. In the fresh curds, 2 dominant water fractions were present, characterized by average spin-spin relaxation times (T2) of 14 and 86 to 89 ms, respectively. These 2 fractions of low- and high-molecular-mobility water were similar in all cheeses and presumed to represent water associated with the casein matrix and water present in the pores. A few hours after manufacture, cheeses made with phospholipase showed decreased T2 of the high-mobility fraction, indicating improved water-holding capacity. It is suggested that lysophospholipids released from the fat globule membranes act as surface-active agents in the cheese curd, helping emulsification of water and fat during processing and reducing syneresis. During 3 wk of storage after manufacture, the mobility of both water fractions increased in all cheeses, but was highest in the cheeses made with phospholipase. The increase in mobility during the first weeks of storage has earlier been ascribed to structural changes in the protein matrix, which in principle could be accelerated because of the higher moisture content. However, the microstructure of phospholipase-treated cheese was investigated by confocal laser scanning microscopy and found to be very similar to the control cheese during processing and up to 28 d of storage. In addition, flowability, stretchability, and browning were acceptable and similar in all the manufactured cheeses. Thus, phospholipase hydrolysis of cheese milk improved the cheese yield without changing the cheese microstructure, and resulted in cheese with functional properties that were identical to traditional Mozzarella cheese.

Demonstration of lanthanum in liver cells by energy-dispersive X-ray spectroscopy, electron energy loss spectroscopy and high-resolution transmission electron microscopy.

The appearance of lanthanum in liver cells as a result of the injection of lanthanum chloride into rats is investigated by advanced transmission electron microscopy techniques, including electron energy loss spectroscopy and high-resolution transmission electron microscopy. It is demonstrated that the lysosomes contain large amounts of lanthanum appearing in a granular form with particle dimensions between 5 and 25 nm, whereas no lanthanum could be detected in other surrounding cellular components.

Effects of strontium on the physicochemical characteristics of hydroxyapatite.

In a previous experimental study using a chronic renal failure rat model, a dose-related multiphasic effect of strontium (Sr) on bone formation was found that could be reproduced in an in vitro set-up using primary rat osteoblasts. The results from the latter study allowed us to distinguish between a reduced nodule formation in the presence of an intact mineralization at low Sr-doses (1 microg/ml) and an interference of the element with the hydroxyapatite (HA) formation at high doses (20-100 microg/ml). To further investigate the latter effect of Sr on physicochemical bone mineral properties, an in vitro study was set up in which the UMR-106 rat osteosarcoma cell line was exposed to Sr, added to the cell culture medium in a concentration range varying between 0-100 microg/ml. Temporal growth and functionality of the culture was investigated by measurement of the alkaline phosphatase activity and calcium (Ca) concentration in the culture medium (used as an index of Ca-incorporation, i.e., HA formation) at various time points. At the end of the culture period (14 days post-confluence), samples of the mineralized cultures were taken for further analysis using X-ray diffraction (XRD) and Fourier Transform Infra-Red Spectroscopy (FTIR). Synthetic HA doped with various Sr concentrations (based on the cell culture and previous experimental studies and yielding Sr/(Sr + Ca) ratios ranging from 0-60%), was prepared and examined for crystal growth and solubility. Crystal size was assessed using scanning electron microscopy (SEM). Ca incorporation indicated a reduced mineralization in the 20 and 100 microg/ml Sr groups vs. controls. Sr-doped synthetic HA showed a significant dose-dependent reduction in crystal growth, as assessed by SEM, and an increase in solubility, apparent from 12.7% Sr/(Sr + Ca) on. Moreover, in both mineralized cultures and synthetic HA, XRD and FTIR analysis showed a reduced crystallinity and altered crystal lattice at similar concentrations. These new data support our previous in vivo and in vitro findings and point to a potential physicochemical interference of Sr with HA formation and crystal properties in vivo.

Re-evaluation and modification of the Stuivenberg Hospital Acute Renal Failure (SHARF) scoring system for the prognosis of acute renal failure: an independent multicentre, prospective study.

BACKGROUND: A prognostic scoring system for hospital mortality in acute renal failure (Stuivenberg Hospital Acute Renal Failure, SHARF score) was developed in a single-centre study. The scoring system consists of two scores, for the time of diagnosis of acute renal failure (ARF) and for 48 h later, each originally based on four parameters (age, serum albumin, prothrombin time and heart failure). The scoring system was now tested and adapted in a prospective study. METHODS: The study involved eight intensive care units. We studied 293 consecutive patients with ARF in 6 months. Their mortality was 50.5%. The causes of ARF were medical in 184 (63%) patients and surgical in 108 (37%). In the latter group, 74 (69%) patients underwent cardiac and 19 (18%) vascular surgery. RESULTS: As the performance of the original SHARF scores was much lower in the multicentre study than in the original single-centre study, we re-analysed the multicentre data to customize the original model for the population studied. The independent variables were the score developed in the original study plus all additonal parameters that were significant on univariate analysis. The new multivariate analysis revealed an additional subset of three parameters for inclusion in the model (serum bilirubin, sepsis and hypotension). For the modified SHARF II score, r(2) was 0.27 at 0 and 0.33 at 48 h, respectively, the receiver operating characteristic (ROC) values were 0.82 and 0.83, and the Hosmer-Lemeshow goodness-of-fit P values were 0.19 and 0.05. CONCLUSION: After customizing and by using two scoring moments, this prediction model for hospital mortality in ARF is useful in different settings for comparing groups of patients and centres, quality assessment and clinical trials. We do not recommend its use for individual patient prognosis.

Renovascular hypertension: diagnostic and therapeutic challenges.

Atherosclerotic renal artery stenosis (ARAS) is associated with two common clinical syndromes: renovascular hypertension and ischemic nephropathy, which often coexist. The ensuing renovascular disease constitutes the fastest-growing etiology of end-stage renal disease. Diagnostic work-up for hemodynamical significant renal artery stenosis should be restricted to patients suspected to be at moderate or high risk for renovascular disease. Patients at moderate risk should first undergo a screening test, like Doppler ultrasonography or captopril-enhanced scintigraphy. In case of a positive screening test, renal artery imaging with either spiral computed tomography angiography or magnetic resonance angiography with Gadolinium is indicated. Patients at high risk for renovascular disease may be directly referred for intra-arterial renal artery angiography, the golden standard diagnostic procedure. A renal artery stenosis with narrowing of > 50-60% of the lumen, is considered hemodynamically significant, and may be suitable for treatment with angioplasty or angioplasty plus stent placement (in case of osteal renal artery stenosis). The therapeutic approach of the hypertensive patient with a hemodynamically significant renal artery stenosis is currently a matter of great debate. In any case optimal medical therapy with antihypertensive, lipid-lowering, and platelet-inhibiting drugs should be instituted, since such approach may not only prevent the progression to end-stage renal disease, but may also prevent the progression of extra-renal vascular disease, which affects the majority of these patients. Current evidence suggests that angioplasty (with additional stent placement in case of osteal renal artery stenosis) may benefit a subset of patients with significant RAS, i.e. patients with a resistance index < 80% at the level of the segmental renal arteries, and patients with bilateral RAS or patients with unilateral RAS with a unique functioning kidney. Prospective, randomized and controlled studies with clearly defined clinical endpoints are needed to better define the absolute and relative indications of angioplasty (plus stenting) in the setting of renal artery stenosis.

Renal impairment in patients with inflammatory bowel disease: association with aminosalicylate therapy?

BACKGROUND: In recent years, several case reports have been published suggesting an association between the use of 5-aminosalicylic acid (5-ASA) in patients with inflammatory bowel disease (IBD) and the development of chronic tubulo-interstitial nephritis. Apart from lesions associated to 5-ASA treatment, however, it is clear that IBD itself may also induce renal impairment, albeit the frequency is unknown. METHODS: During 1 year, all IBD patients seen at the outpatient clinic of 27 European centres of gastro-enterology were registered and screened for renal impairment controlling for a possible association with 5-ASA therapy. Patients were questioned about their medical and drug history and their IBD disease activity. Renal screening (calculated creatinine clearance) was performed at baseline, after 6 and 12 months. RESULTS: Included patients (n = 1,529) had a mean age of 39 (range 14-98), 56% had Crohn's disease, 42% ulcerative colitis and 2% indeterminate colitis. Half of the patients used 5-ASA during the study period. Decreased creatinine clearance was observed in 34 patients, among them 13 with chronic renal impairment. Comparing patients with and without renal impairment, no difference could be observed in 5-ASA consumption. In contrast, patients with renal impairment were significantly older, had a lower body mass index and showed a higher frequency of male sex, bowel resection and stoma. CONCLUSION: Although the association between 5-ASA therapy and chronic tubulo-interstitial nephritis is clearly described in several case reports, this prospective study came to the reassuring conclusion that renal impairment in IBD patients is not frequently observed and is rarely associated with 5-ASA therapy.

[Misconduct in clinical scientific investigations]. / Wangedrag in klinisch-wetenschappelijk onderzoek.

The most important ways of misconduct in clinical scientific research are falsifying results, plagiarize and over-interpretation. Motives are prestige, money, pressure of time and conflict of interests. The "publish or perish" phenomenon and the sometimes difficult attainable deadline play an important role. Furthermore, there is a "gray-zone" in which clinical scientific researchers are influenced by the pharmaceutical industry, leading to the writing of tendentious publications. Few data are available concerning the frequency of misconduct. In general, one may say that the phenomenon is underestimated. The number of professional organizations for the detection of misconduct and to start a balanced investigation procedure of this phenomenon is limited. An exception is "Office of Research Integrity" in the US that does pioneering work in the field. Some of the better journals in the profession are making serious efforts to detect misconduct (e.g. New England Journal of Medicine, British Medical Journal). To prevent misconduct the following measures can be considered: education concerning the topic in the faculties of medicine, biomedical sciences and pharmaceutics sciences; extension of the competences of the ethical committees; realistic financing of research and the establishing of a "clinical scientific fund", without any relation with the pharmaceutical industry, for the support of self-generated clinical project after 'peer review'. Finally, the questions can be raised if the Royal Academy of Medicine (Belgium) could not play a role in this important matter.

Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients.

Mycophenolate mofetil (MMF) is one of the new immunosuppressive drugs used in renal transplantation. MMF inhibits the de novo purine synthesis. Since this purine synthesis in lymphocytes entirely depends on the de novo pathway, MMF is considered to cause a selective inhibition of T- and B lymphocytes. Recently, 4 transplant patients out of 30 developed a severe anemia in the early post-transplantation period. Their immediate post-transplantation immunosuppression consisted of corticosteroids, cyclosporine and MMF. They all received anti-T-lymphocyte globulin (ATG) as induction treatment or because of rejection. In all 4 patients, iron supplementation and a treatment with erythropoietin were started. Blood loss, deficiencies, hemolysis, drug interactions or viral infections were excluded as causes of the anemia. Bone marrow biopsies were carried out, showing pure red cell aplasia that was ascribed to the use of MMF. Cessation or reduction of MMF was followed by a hematological improvement after 5-9 days. We hypothesized that MMF has a broader antiproliferative effect than its proposed lymphocyte-specific effect.

Staging disease severity in pathologically confirmed cases of frontotemporal dementia.

OBJECTIVE: To devise a staging scheme for addressing the severity of atrophy in patients with pathologically proven frontotemporal dementia (FTD) and determine any relationship with clinical indices. METHODS: Twenty-four cases with clinical and pathologic features of FTD were selected using standard inclusion and exclusion criteria from 125 dementia cases collected in Sydney, Australia, over an 8.5-year period. Patterns of gross atrophy were determined in two coronal brain slices. Reproducibility of a four-stage severity scheme was tested. Nonparametric statistics were used to determine relationships between the stage of atrophy and clinical indices (age at death, duration from diagnosis, and clinical severity at death). RESULTS: The FTD cases studied could be reliably grouped (kappa = 0.97) into four progressively severe stages of global atrophy. Initial mild atrophy occurred in the orbital and superior medial frontal cortices and hippocampus (stage 1), progressed to involve the other anterior frontal regions, temporal cortices, and basal ganglia (stage 2), then involved all remaining tissue in these coronal slices (stage 3), until very marked atrophy was observed in all areas (stage 4). These stages correlated with disease duration and clinical dementia severity, lending validity to the progressive nature of the staging scheme. CONCLUSIONS: The authors have identified a reproducible staging system for the severity of gross atrophy in cases of FTD. This staging scheme provides the required framework to compare different research indices and determine correlates relating to time and disease progression in FTD-information necessary to determine core disease processes and etiologic factors.